The occurrence of tumor is an evolution process of multi-factors and multi-stages, involving mutation and epigenetic changes of multiple genes such as oncogene, anti-oncogene and DNA damage repair gene. Strictly speaking, epigenetics is defined as a combination of genetic mechanisms capable of altering genome function in addition to the direct alteration of the DNA sequence. Herein, “epigenetics” refers broadly to elements of chromatin structure that control genome function, regardless of whether the control is heritable. Epigenetic or chromatin-based regulation plays an important role in gene expression in normal physiological function or in cancer evolution
Polycomb group protein (PcG) is an important protein factor involved in the negative regulation of chromatin gene epigenetics. In mammals, PcG is mainly divided into two types with different structures and functions: polycomb repressive complex 2 (PRC2) and polycomb repressive complex 1 (PRC1). The histone methyltransferase encoded by the EZH2 gene is the catalytic component of polycomb repressive complex 2 (PRC2) and exerts the trimethyltransferase activity on the lysine 27 (H3K27) of histone H3 to generate H3K27me3 by means of the SET domain of the EZH2 subunit. It promotes transcriptional repression by means of various mechanisms including the urgent recruitment of DNA methyltransferases (DNMT) and PRC1 that ubiquitinates H2AK119. The codon mutation at codon 641 of EZH2, the most common mutation hotspot, is a gain-of-function mutation leading to an enhanced trimethylation of histone H3K27, and plays an important role in the tumorigenesis of GCB-type diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Recurrent somatic mutations in the SET domain of EZH2 are common in patients with diffused large B cell lymphomas (DLBCL). In addition, EZH2 overexpression is common in a variety of tumor types with poor prognosis, including cancers, lymphomas and soft tissue sarcomas etc. EZH2 expression in synovial sarcoma is associated with high H3K27 trimethylation. EZH2 levels are abnormally elevated in cancer tissues compared to normal tissues, and EZH2 is most highly expressed in advanced cancers or poor prognosis. In some types of cancers, EZH2 overexpression occurs simultaneously with amplification of the EZH2 gene. A large number of si/shRNA experimental studies show that reduction of EZH2 expression in tumor cell lines can inhibit tumor cell proliferation, migration, and invasion, or angiogenesis, and lead to apoptosis.
Patent applications disclosing EZH2 selective inhibitors include WO2012005805, WO2012050532, WO2012118812, WO2012142513, WO2012142504, WO2013049770, WO2013039988, WO2013067300, WO2015141616, and WO2011140325, etc.
EZH2 inhibitors as drugs have promising application prospects in the medical industry. However, there is still a need to develop new EZH2 inhibitors for achieving better therapeutic effects in tumors and cancers, and which better meets the maket demand.